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Molecular and Cellular Biology, August 2005, p. 7170-7180, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7170-7180.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3-Dependent Phosphorylation of Mdm2 Regulates p53 Abundance

Roman Kulikov, Karen A. Boehme, and Christine Blattner*

Institut für Genetik, Forschungszentrum Karlsruhe, P.O. Box 3640, 76021 Karlsruhe, Germany

Received 17 December 2004/ Returned for modification 28 January 2005/ Accepted 24 May 2005

The Mdm2 oncoprotein regulates abundance and activity of the p53 tumor suppressor protein. For efficient degradation of p53, Mdm2 needs to be phosphorylated at several contiguous residues within the central conserved domain. We show that glycogen synthase kinase 3 (GSK-3) phosphorylated the Mdm2 protein in vitro and in vivo in the central domain. Inhibition of GSK-3 rescued p53 from degradation in an Mdm2-dependent manner while its association with Mdm2 was not affected. Likewise, inhibition of GSK-3 did not alter localization of p53 and Mdm2 or the interaction of Mdm2 and MdmX. Ionizing radiation, which leads to p53 accumulation, directed phosphorylation of GSK-3 at serine 9, which preceded and overlapped with the increase in p53 levels. Moreover, expression of a GSK-3 mutant where serine 9 was replaced with an alanine reduced the accumulation of p53 and induction of its target p21WAF-1. We therefore conclude that inhibition of GSK-3 contributes to hypophosphorylation of Mdm2 in response to ionizing rays, and in consequence to p53 stabilization.

* Corresponding author. Mailing address: Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, P.O. Box 3640, 76021 Karlsruhe, Germany. Phone: 49-7247-822634. Fax: 49-7247-823354. E-mail: christine.blattner{at}itg.fzk.de.

Molecular and Cellular Biology, August 2005, p. 7170-7180, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7170-7180.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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